Process for the preparation of heterocyclic pentalene derivatives

ABSTRACT

A process for preparing heterocyclic pentalene derivative having formula (I): wherein w is a sulfur atom (S), an oxygen atom (O) or a NR or PR group, wherein R is an hydrocarbon group; R 1 , R 2 , R 3 , and R 4 , equal to or different from each other, are hydrogen atoms or hydrocarbon groups; said process comprising the following steps: a) contacting a compound of formula (II) T is a OR, NR 2 , CCI 3 , CF 3 , Cl, Br, I, imidazolil or pirazolyl radical; with at least one molar equivalent of a vinyl compound of formula (III): wherein M is MgHal, Li, K, ZnHal, wherein Hal is chlorine, bromine or iodine; (II), (III) b) treating the compound of formula obtained in step a) with a Bronsted acid; c) treating the compound obtained in step b) with a reducing agent; and d) dehydrating the alcohol obtained in step c) in order to obtain the compound of formula (I).

[0001] The present invention relates to a new process for preparingheterocyclic pentalenes derivatives of formula:

[0002] wherein R¹, R², R³ and R⁴ represent hydrogen or hydrocarbon restsand W is an oxygen atom, a sulfur atom or a NR or PR group and R is anhydrocarbon rest.

[0003] Heterocyclic pentalenes are well known in the art for varioususes. For example substituted thiophenes and b, d-ortho-fused thiophenesare used as reference materials in the analysis of sulphur-containingsubstances of fossil raw materials, such as mineral oils, coal,carbonaceous oils, shale oils and tar sands, as model systems forstudying the desulphurisation of the aforementioned fossil rawmaterials, also on a technical scale, as oxidation inhibitors, forexample in lubricants and as active substances in the fields involvingbiocides.

[0004] Recently they have been used for the preparation of metallocenecomplexes useful as catalysts for the polymerization of olefins. Forexample in J. Am. Chem. Soc. 1998, 120, 10786-10787 Ewen et al. describemetallocene compounds containing thiopentalene and azapentalenederivatives. Also PCT/EP00/12406 describes metallocene compoundscontaining thiopentalenes ligands. Catalyst based on these compoundsproduce polypropylene having a high degree of isotacticity. However thesynthesis of these compounds involves several steps with low yields and,moreover, some derivatives are not accessible according to the routesproposed in these documents.

[0005] Therefore, a new process that permits to obtain these compoundsin higher yields and with simple steps would be desirable.

[0006] The applicant has now found a new process that permits toovercome the above drawbacks and, moreover, to obtain a broader class ofcompounds.

[0007] An object of the present invention is a process for preparingheterocyclic pentalene derivatives having formula (I):

[0008] wherein

[0009] W is a sulfur atom, an oxygen atom or a NR or PR group wherein Ris a linear or branched saturated or unsaturated C₁-C₂₀-alkyl,C₃-C₂₀-cycloalkyl, C₆-C₂₀-aryl, C₇-C₂₀-alkylaryl or C₇-C₂₀-arylalkylradical, optionally containing heteroatoms belonging to groups 13-17 ofthe Periodic Table of the Elements; preferably the group NR is N-methylor N-phenyl; and the group PR is P-methyl or P-phenyl; more preferably Wis a sulfur atom;

[0010] R¹, R², R³ and R⁴, equal to or different from each other, arehydrogen atoms or a linear or branched saturated or unsaturatedC₁-C₂₀-alkyl, C₃-C₂₀-cycloalkyl, C₆-C₂₀-aryl, C₇-C₂₀-alkylaryl orC₇-C₂₀-arylalkyl radical, optionally containing heteroatoms belonging togroups 13-17 of the Periodic Table of the Elements; or R¹ and R² and/orR³ and R⁴ can form a C₄-C₇ ring optionally containing O, S, N, P or Siatoms, said ring optionally bearing C₁-C₂₀ alkyl substituents or beingoptionally fused with a C₄-C₇ ring optionally containing O, S, N, P orSi atoms, such as a benzene or a cyclopentadiene ring; preferably R¹ ishydrogen, a C₁-C₂₀-alkyl or C₇-C₂₀-arylalkyl radical; more preferably R¹is a methyl, a phenyl or a C₁-C₁₀ alkyl substituted phenyl radical;preferably R² is hydrogen or a C₇-C₂₀-arylalkyl radical; more preferablyR² is a phenyl or a C₁-C₁₀ alkyl-substituted phenyl radical; preferablyR³ is hydrogen or a C₁-C₂₀-alkyl radical; and preferably R⁴ is hydrogen,a C₁-C₂₀-alkyl or C₇-C₂₀-arylalkyl radical; more preferably R⁴ is amethyl, or a phenyl radical;

[0011] said process comprising the following steps:

[0012] a) contacting a compound of formula (II):

[0013] wherein R¹ and R² are defined as above and T is a OR, NR₂, OH,CCl₃, CF₃, Cl, Br, I, imidazolyl or pirazolyl radical;

[0014] with at least one molar equivalent of a vinyl compound of formula(III):

[0015] wherein R³ and R⁴ are defined as above and M is MgHal, Li, K,ZnHal, wherein Hal is chlorine, bromine or iodine; to form a compound offormula (IV):

[0016] b) treating the compound of formula (IV) with a Brønsted acid toform a compound of formula (V):

[0017] c) treating the compound of formula (V) with a reducing agent toform the correspondent alcohol of formula (VI);

[0018] and

[0019] d) dehydrating the alcohol of formula (VI).

[0020] Non limitative examples of compounds of formula (I) are:

[0021] Compounds of formula (II) used in step a) can be prepared withmethods generally known in the art. For example when W is a sulfur atomthese compounds can be prepared according to the process described in J.Chem Soc. Perkin 1, 1976, vol. 22, 2355-2360.

[0022] Compounds of formula (III) can be easily prepared starting fromthe correspondent vinyl bromide or they can be purchased as such

[0023] Step a) is carried out at a temperature range of from −78 C. to100° C., preferably from −20° C. to 20° C. Usually aprotic solvents areused, such as toluene, diethyl ether, hexane, tetrahydroflran, dimethylformamide, etc. The product obtained from step a) is purified by processknown in the art such as filtration, crystallization, chromatography,distillation; otherwise it is used as such.

[0024] Preferably in the compound of formula (II) T is a NR₂ group; morepreferably T is a N(Me)₂ or a N(Et)₂ radical. In the compound of formula(III) preferably the group M is MgBr or Li. Examples of Brønsted acidused in step b) are methanesulphonic acid, sulfuric acid, phosphoricacid, polyphosphoric acid or P₂O₅/methansulfuric acid. Preferablymethanesulphonic acid or sulfuric acid are used. The reaction ispreferably carried out in water or in an organic solvent such asdichloromethane, diethyl ether, tetrahydrofuran, dimethyl formamide, orin mixtures of water and organic solvents optionally in the present of aphase transfer agent. The reaction is carried out at a temperature rangefrom 0° C. to 100° C. The amount of acid in step b) depends from theacid, usually a large excess of acid is used for example from 10 to10000 equivalents or more.

[0025] The product obtained from step b) is purified by processes knownin the art such as filtration, crystallization, chromatography,distillation; otherwise it is used as such.

[0026] Examples of reducing agents that can be used in step c) can befound in “Comprehensive Organic Transformations” ed. 1989 VCH Publisherspages 527-552. For example LiAlH₄, AlH₃, NaBH₄ or LiHAl(OtBu)₃ can beused. Preferably LiAlH₄ is used.

[0027] The type of solvent used in step c) depends from the reducingagent used. In the case of LiAlH₄, AlH₃, NaBH₄ or LiHAl(OtBu)₃ thereaction is carried out in an aprotic solvent such as toluene, diethylether, hexane, tetrahydrofuran, dimethyl formamide, at a temperaturerange of from −78 C to 100° C., preferably from 0° C. to 80° C. Theproduct obtained from step c) is purified by processes known in the artsuch as filtration, crystallization, chromatography, distillation;otherwise it is used as such.

[0028] Step d) is carried out by treating the alcohol of formula (VI)with a dehydrating agent. Examples of dehydrating agent can be found in“Comprehensive Organic Transformations” ed. 1989 VCH Publishers pages151-153. Example of dehydrating agent are p-toluenesulfonic acid,sulfuric acid, hydrochloric acid and iodine. Preferably p-toulensulfonicacid and iodine are used.

[0029] The amount of dehydrating agent depends from the dehydratingagent used. It can vary from one equivalent to a large excess such as1000 equivalents and more.

[0030] The type of solvent used in step d) depends from the dehydratingagent used. In the case of p-toulensulfonic acid the reaction is carriedout in an aprotic solvent such as toluene, diethyl ether, hexane,tetrahydrofuran, dimethyl formamide, at a temperature range of from 0°C. to 100° C., preferably from 20° C. to 80° C. The product obtainedfrom step d) is purified by processes known in the art such asfiltration, crystallization, chromatography, distillation. A furthermethod for purifying compounds obtained in step d) is treating the crudereaction product with at least one equivalent of an organolithiumcompound such as butylithium, methylfithium, tertbuthylithium andphenyllithium and filtering the obtained salt.

[0031] Steps a), b, c) and d) of the process of the present inventionmay be carried out in sequence without purification of the intermediateproducts.

[0032] Preferably steps c) and d) are carried out “one pot”, i.e.without purification of the alcohol of formula (VI).

[0033] Compounds of formula (I) can be used as ligands for the synthesisof metallocene complexes, such as those described in WO 01/44318. Thesecomplexes are useful as catalyst components for polymerizingalpha-olefins. The syntheses of the metallocene compounds starting fromthe compounds of the present invention are described in the abovementioned application. Generally, the compounds of formula (I) can betreated with a base and then contacted with a compound of formula YL′Cpwherein Y is halogen, preferably chlorine, L′ is a suitable bridge andCp is a substituted or unsubstituted cyclopentadienyl radical. Theobtained bridged ligand is then treated with two equivalents of a baseand contacted with the compound of formula ML″₄ wherein M is titanium,zirconium or hafnium and L is generally halogen, preferably chlorine.For unbridged metallocene compounds the compound of formula (I) istreated with a base and then the correspondent anion is contacted with acompound of formula ML″₄.

[0034] The following examples are given for illustrative purposes andare not intended to limit the scope and spirit of the invention.

EXAMPLES

[0035] General Procedures.

[0036] Operations moisture sensitive were performed under nitrogen byusing conventional Schlenk-line techniques. Solvents were purified bydegassing with N₂ and passing over activated (8 hours, N₂ purge, 300°C.) Al₂O₃, and stored under nitrogen. n-BuLi (Aldrich) was used asreceived.

Example 1 Synthesis of 2,3-diphenyl-5-methyl-6H-cyclopenta[b]thiophene

[0037]

[0038] Preparation of the Compound of Formula (II)

Synthesis of 2,3-Diphenyl-thienylcarbonyc acid

[0039]

[0040] 30.8 g (0.1 mol) of 2,3-diphenyl-5-carbetoxythiophene (preparedanalogously to 2-methyl-3-phenyl-5-carbetoxythiophene with 70-80% yieldfrom dezoxybenzoin) was treated with solution of 20 g NaOH in 50 mlwater+50 ml ethanol. Resulting mixture was refluxed in 3 h and then wastreated with 100 ml water. Aqueous phase was collected, added with HClaq. up to pH=3. White solid was isolated by filtration, washed with 100ml water and dried. Yield 100%.

[0041]¹H NMR (Dimethylsulfoxide (DMSO)-d₆): 7.76 (s, 1H), 7.40-7.20 (m,10H), 3.5 (br.s., water+acidic proton)

Synthesis of 2,3-Diphenyl-thienylcarbonyc acid dimethylamide

[0042]

[0043] 10 g (36 mmol) of acid, 5.5 ml SOCl₂ (75 mmol), 0.1 mldimethylformamide (DMF) and 50 ml of benzene were placed into the bulband refluxed in 2 h. Then the mixture was evaporated. Resulting oil wasdissolved in 10 ml of tetrahydrofuran (THF) and this solution was addeddropwise to 30 ml 33% aqueous Me₂NH at 0° C. The mixture was stirred in30 min. The precipitate was isolated, washed with water and dried. Yield10 g (92%).

[0044]¹H NMR (CDCl₃): 7.45 (s, 1H), 7.40-7.20 (m, 10H), 3.40-3.20(br.s., 6H)

[0045] Step a) 1-(4,5-Diphenyl-2-thienyl)-2-methyl-2-propen-1-on

[0046] 10 g (33 mmol) of 2,3-Diphenyl-thienylcarbonic acid dimethylamidewas dissolved in 15 ml THF and the resulting solution was added dropwiseto solution of propenylmagnesium bromide prepared from 0.78 g Mg (33mmol) and 4 g 2-bromopropene (33 mmol) in 50 ml THF at −40° C. Themixture warmed to r.t. and was stirred in 4 h. The resulting solutionwas poured into 100 ml of 5% aqueous HCl. The organic layer wascollected, washed with water, dried over MgSO₄ and evaporated to giveyellow-reddish oil. Yield 9.5 g (100%). The product is contaminated with5-10% of starting amide (by NMR) and can be used without furtherpurification.

[0047] Step b)5-Methyl-2,3-diphenyl-4,5-dihydro-6H-cyclopenta[b]thiophen-6-on

[0048] Solution from previous experiment was poured into 80 mlmethanesulphonic acid (can be replaced by H₂SO₄) at 65° C. After 30 minof stirring at reflux the resulting mixture was poured into 400 mlwater/300 ml dichlorometane mixture. The organic phase was collected,washed with aq. NaHCO₃ up to neutral reaction and dried over MgSO₄. Theresulting solution was evaporated to give 8.8 g viscous oil. Thissubstance either have to be purified by chromatography on silica gelwith benzene as an eluent (R_(f) of the product is ˜0.15) or can be usedas is.

[0049]¹H NMR (CDCl³): 7.40-7.20 (m, 10H), 3.20 (dd, 1H), 3.06 (quintetof doublets, 1H), 2.67 (dd, 1H), 1.44 (d, 3H)

[0050] Steps c) and d) 5-Methyl-2,3-diphenyl-4H-cyclopenta[b]thiophene

[0051] Solution of 7 g (0.023 mol)5-methyl-2,3-diphenyl-4,5-dihydro-6H-cyclopenta[b]thiophen-6-on in 200ml ether was treated with 0.24 g (0.0063 mol) LiAlH₄ in 100 ml ether.The mixture was stirred in 30 min and then was poured in 300 ml of 10%NH₄Cl. The organic phase was collected, dried over MgSO₄ and evaporated.Resulting alcohol (6.7 g, 95%) was dissolved in 350 ml benzene. To thissolution 0.25 g p-toluenesulphonic acid and a few crystals of2,6-di(tert-butyl)phenol were added. The resulting mixture was refluxedin 10 min, then was cooled to r.t., washed with saturated aq. NaHCO₃ andwater. The solution so-obtained was dried over MgSO₄ and evaporated. Theresidue was recrystallized from hexane to give 4.2 g (67% from ketone)of the product as yellowish crystalline solid.

[0052]¹H NMR (C₆D₆): 7.45 (d, 2H), 7.31 (d, 2H), 7.15-6.90 (m, 6H), 6.20(quintet, 1H); 2.73 (br.s, 2H); 1.80 (s, 3H)

Example 2 Synthesis of 2-methyl-3,5-diphenyl-6H-cyclopenta[b]thiophene

[0053]

[0054] Preparation of the Compound of Formula (II)

Synthesis of 3-chloro-2-phenyl-2-butenal

[0055]

[0056] 0.375 mol (35 mL) of POCl₃ was added at 0° C. to a 0.45 mol (35mL) of DMF. At the end of the addition, the mixture was allowed to warmup to room temperature and stirred for 30 min. Then it was cooled againto 0° C. and carefullly treated with 0.15 mol (20.1 g) of phenylacetone.The resulting reaction mixture was stirred at the same temperature for 1h and then at 60-70° C. in additional 4 hours (the reaction wasmonitored by NMR). The resulting viscous solution was poured into amixture of ice and aqueous sodium acetate (150 g). Product was extractedwith CH₂Cl₂ (3×50 mL). The organic phase was separated, washed withwater until neutral pH, dried over MgSO₄ and evaporated to dryness. Theresidue represents chloroaldehyde as a mixture of two forms (ratio offorms depends on the duration of chlorocarbonylation). It was usedwithout further purification. Yield 19.2 (71%).

[0057]¹H-NMR (CDCl₃): 10.47(s) and 10.15(s) (1H, CHO); 7.40-7.00 (groupof multiplets, 5H, aromatic CH); 2.79(s) and 2.32(s) (3H, CH₃).

[0058] Note: do not use distillation to purify the product!

Synthesis of 5-methyl-4-phenyl-2-thiophene-ethylcarboxylate

[0059]

[0060] Ethyl-2-mercaptoacetate (45.8 mmol, 5.0 mL) was added at 0° C. toa solution of sodium ethoxide (46 mmol, 3.13 g) in 50 mL of ethanol andthe resulting mixture was stirred at the same temperature for 30 min.Then 3-chloro-2-phenyl-2-butenal (45.8 mmol, 8.3 g) was added andstirring was continued overnight. The resulting product was refluxed for2 h, cooled to room temperature and diluted in 100 mL of water. Theorganic layer was collected and the water layer was extracted withCH₂Cl₂ (3×50 mL). The combined organic layers were dried over MgSO₄,evaporated to dryness and the residue was used in the next step withoutfurther purification.

Synthesis of 5-methyl-4-phenyl-2-thiophenecarboxylic acid

[0061]

[0062] The 5-methyl-4-phenyl-2-thiophene-ethylcarboxylate coming fromthe previous step was added to a 30% solution of sodium hydroxide in 100mL of ethanol and the resulting mixture was refluxed for 2 h. Then itwas diluted in water and extracted with 50 mL of benzene. The waterphase was isolated, acidified and the mixture was filtered. Theprecipitate was dried under P₂O₅. Yield 9.5 g (95% towards3-chloro-2-phenyl-2-butenal).

[0063]¹H-NMR (CDCl₃): 12.00-10.00 (br.s, 1H, COOH); 7.87 (s, 1H,thiopheneCH); 7.50-7.35 (m, 5H, phenylCH); 2.58 (s, 3H, CH3).

Synthesis of 2-Methyl-3-phenyl-thienylcarbonyc dimethylamide

[0064]

[0065] 21.8 g (0.1 mol) of acid, 10.9 ml SOCl₂ (0.5 mmol), 0.5 ml DMFand 150 ml of dichloromethane were placed into the bulb and refluxed in2 h. Then the mixture was evaporated. Resulting oil was dissolved in 20ml THF and this solution was added dropwise to 50 ml 33% aqueous Me₂NHat 0° C. The mixture was stirred in 30 min. The resulting emulsion waspoured into 500 ml of water. Product was extracted with 2×50 mldichloromethane. Solution was washed with water, dried over magnesiumsulfate and evaporated to give brown viscous liquid that tends tocrystallize. Yield 28 g (81%).

[0066]¹H NMR (CDCl₃): 7.45 (s, 1H), 7.40-7.20 (m, 10H), 3.40-3.20(br.s., 6H)

[0067] Step a) 1-(5-Methyl-4-phenyl-2-thienyl)-2-phenyl-2-propen-1-on

[0068] 23.3 g (100 mmol) of 2-methyl-3-phenyl-thienylcarbonic aciddimethylamide was mixed with 100 ml ether and the resulting suspensionwas added in some portions at 0° C. to solution of 1-stiryllitiumprepared from 62 ml 1.6M BuLi in hexane (100 mmol) and 27 g1-bromostyrene (150 mmol) in 200 ml ether. The mixture warmed to r.t.and was stirred in 1 h. The resulting solution was poured into 500 ml of5% aqueous HCl. The organic phase was collected, separated frominsoluble impurities (these impurities presumably are due to the use ofLi-derivative instead of Mg derivative in the previous case), washedwith water, dried over MgSO₄ and evaporated to give yellow oil. Yield ofcrude product 15 g (52%). The product can contaminated with 5-10% ofstarting amide (by NMR) and can be used without further purification.

[0069]¹H NMR (CDCl³): 7.61 (s, 1H), 7.55-7.35 (m, 10H), 6.03 (s, 1H),5.82(s, 1H), 2.59 (s., 3H

[0070] Step b)2-Methyl-3,5-diphenyl-4,5-dihydro-6H-cyclopenta[b]thiophen-6on

[0071] Vinyl-ketone obtained in previous experiment was dissolved in 20ml of dichloromethane and resulting was poured into 50 mlmethanesulphonic acid heated to 65° C. After 30 min of stirring atreflux the resulting mixture was poured into the mixture 0.31water/ice/200 ml dichlorometane. The organic phase was collected, washedwith water, then with aq. NaHCO₃ up to neutral reaction and dried overMgSO₄. The resulting solution was evaporated to give 14 g of viscousoil. This oil crystallizes on standing. This substance can be used forfurther steps (reduction by LiAlH₄ followed by dehydration withoutspecial purification.

[0072]¹H NMR (CDCl₃): 7.55-7.20 (m, 10H), 4.15 (dd, 1H); 3.50 (dd, 1H);3.07 (dd, 1H), 261 (s., 3H)

[0073] Steps c) and d) 2-Methyl-3,5-diphenyl-4H-cyclopenta[b]thiophene

[0074] Solution of 14 g (47 mmol)2-Methyl-3,5-diphenyl-4,5-dihydro-6H-cyclopenta[b]thiophen-6-on in 150ml ether was treated with 0.63 g (16 mmol) LiAlH₄ in 100 ml ether. Themixture was stirred in 30 min and then was poured in 300 ml of 10%NH₄Cl. The organic phase was collected, dried over MgSO₄ and evaporated.Resulting alcohol (13.4 g, 95%) was poured into solution 1 gp-toluenesulphonic acid in 11 toluene at 65° C. The resulting mixturewas stirred in 20 min at 80° C., then it was cooled to r.t., washed withsaturated aq. NaHCO₃ and water. The solution so-obtained was dried overMgSO₄ and evaporated. The residue was isolated by chromatography onsilica-gel (hexane/CH₂Cl₂ 3/1) to give 6.5 g (53% from ketone) ofyellowish crystalline solid. This solid consists of two isomers ofposition of double bond.

[0075]¹H NMR (CDCl₃): 7.60-7.20 (m, 10H), 7.21(m) and 7.14(m) (1H), 3.83(br.s) and 3.68 (br.s) 2H); 2.60 (s, 3H)

Example 3 Synthesis of 2,3,5-triphenyl-6H-cyclopenta[b]thiophene

[0076]

[0077] Preparation of the Compound of Formula (II)

[0078] 2,3-diphenyl-thienylcarbonic acid dimethylamide was prepared inanalogous manner to 2-Methyl-3-phenyl-thienylcarbonyc dimethylamide withthe exception that the starting compound was dibenzyl ketone instead ofphenylacetone.

[0079] Step a) 1-(4,5-Diphenyl-2thienyl)-2-phenyl-2propen-1on

[0080] 30.7 g (100 mmol) of 2,3-diphenyl-thienylcarbonic aciddimethylamide was mixed with 100 ml ether and the resulting suspensionwas added in some portions at 0° C. to solution of 1-stiryllitiumprepared from 62 ml 1.6M BuLi in hexane (100 mmol) and 27 g1-bromostyrene (100 mmol) in 200 ml ether. The mixture warmed to roomtemperature (r.t.) and was stirred for 1 h. The resulting solution waspoured into 500 ml of 5% aqueous HCl. The organic phase was collected,separated from insoluble impurities, washed with water, dried over MgSO₄and evaporated to give 20.9 g (57%) of crystalline solid. The productcan be contaminated with 5-10% of starting amide (by NMR) and can beused without further purification.

[0081]¹H NMR (CDCl₃): 7.82 (s, 1H), 7.70-7.30 (m, 15H), 6.16 (s, 1H),5.96(s, 1H)

[0082] Note: technical-grade 1-bromo-styrene is available only. It wasdistilled before reaction and was taken in 50% excess.

[0083] Step b) 2,3,5-triphenyl-4,5-dihydro-6H-cyclopenta[b]thiophen-6-on

[0084] Vinyl-ketone obtained in previous experiment was dissolved in 20ml of dichloromethane and resulting was poured into 50 mlmethanesulphonic acid heated to 65° C. After 30 min of stirring atreflux the resulting mixture was poured into the mixture 0.31water/ice/200 ml dichlorometane. The organic phase was collected, washedwith water, then with aq. NaHCO₃ up to neutral reaction and dried overMgSO₄. The resulting solution was evaporated to give 20 g of crystallineproduct. This substance can be used for further steps (reduction byLiAlH₄ followed by dehydration) without special purification.

[0085]¹H NMR (CDCl₃): 7.55-7.20 (m, 15H), 4.25 (dd, 1H); 3.61 (dd, 1H);3.20 (dd, 1H)

[0086] Steps c) and d) 2,3,5-Triphenyl-4H-cyclopenta[b]thiophene

[0087] Solution of 3.7 g (10 mmol)2,3,5-triphenyl-4,5-dihydro-6H-cyclopenta[b]thiophen-6-on in 20 ml etherwas treated with 130 mg (16 mmol) LiAlH₄ in 10 ml ether. The mixture wasstirred in 30 min and then was poured in 50 ml of 10% NH₄Cl. The organicphase was collected, dried over MgSO₄ and evaporated. Resulting alcoholwas poured into solution of 300 mg p-toluenesulphonic acid in 300 mltoluene at 65° C. The resulting mixture was refluxed in 20 min, then itwas cooled to r.t., washed with saturated aq. NaHCO₃ and water. Thesolution so-obtained was dried over MgSO₄ and evaporated. The residuewas isolated by chromatography on silica-gel (hexane/CH₂Cl₂ 3/1) to give2.1 g (60% from ketone) of yellowish crystalline solid.

[0088]¹H NMR (CDCl₃): 7.60 (m, 2H), 7.45-7.25(m, 14H); 3.72 (d, 2H)

Example 3 Synthesis of2,5-dimethyl-3-(4-chloro-phenyl)-6H-cyclopenta[b]thiophene

[0089]

[0090] Preparation of the Compound of Formula (II)

Synthesis of (4-chloro-phenyl)-acetone

[0091]

[0092] 34 g (0.224 mol) (4-chloro-phenyl)benznitryl and 33 ml (0.337mol) ethylacetate was added to the hot solution of 24 g (0.3 mol) sodiumisopropilate in 150 ml isopropanol. Reaction mixture was stirred atreflux in 3 hours then it was cooled to r.t., treated with 20 g (0.3mol) acetic acid and finally diluted with 500 ml water. Organicprecipitate was extracted with 100 ml dichloromethane. Resultingsolution was evaporated to give yellowish solid of p-Cl-phenylacetonethat was used without purification.

[0093]¹H-NMR (CDCl₃): 7.44 (AA′BB′ component, 2H); 7.36 (AA′BB′component, 2H); 4.68 (s, 1H); 2.31 (s, 3H).

[0094] p-Cl-phenylacetone prepared in previous experiment was added insmall portions to 50 ml of concentrated sulfuric acid at 0-5° C. thenthe mixture was heated at stirring to 100° C. in 10 min. Then thereaction mixture was cooled to 0° C., was treated quickly with 250 mlwater and was stirred at 100° C. in 3 hours. The resulting mixture wascooled to r.t., the organic layer was separated and distilled at108-110/10 torr to give 24.5 g (65% from p-Cl-phenylacetone).

[0095]¹H-NMR (CDCl₃): 7.34 (AA′BB′ component, 2H); 7.16 (AA′BB′component, 2H); 3.71 (s, 2H); 2.20 (s, 3H).

Synthesis of 5-methyl-4-(4-Cl-phenyl)1-2-thiophenecarboxylic acid

[0096]

[0097] 17.5 ml (0.19 mol) of POCl₃ was added at 0° C. to a 32 ml (0.44mol) of DMF. At the end of the addition, the mixture was allowed to warmup to room temperature and stirred for 30 min. Then it was cooled againto 0° C. and carefully treated with 24.5 g (0.145 mol) ofp-Cl-phenylacetone. The resulting reaction mixture was stirred at thesame temperature for 1 h and then at 60-70° C. in additional 4 hours.The resulting viscous solution was poured into a mixture of ice andaqueous sodium acetate (150 g). Product was extracted with CH₂Cl₂ (3×50mL). The organic phase was separated, washed with water until neutralpH, dried over MgSO₄ and evaporated to dryness. The residue represents21.5 g (68%) of crude chloroaldehyde that was used as is.

[0098] Ethyl-2-mercaptoacetate (12 g, 0.1 mol) was added at 0° C. to asolution of sodium ethoxide (6.8 g, 0.1 mol) in 150 mL of ethanol andthe resulting mixture was stirred at the same temperature for 30 min.Then chloroaldehyde from the previous experiment (21.5 g, 0.1 mol) wasadded and stirring was continued overnight. The resulting product wasrefluxed for 2 h, cooled to room temperature and then was treated withsolution of 12 g (0.3 mol) NaOH in 20 ml water. The resulting mixturewas refluxed in 1 hour, then it was cooled to r.t. and finally waspoured into 500 ml of water. The resulting mixture was neutralized byaqueous HCl, the precipitate was isolated, washed twice with 200 mlwater and dried. Yield 15.3 g (60%).

[0099]¹H-NMR (DMSO): 7.52 (s, 1H, thiopheneCH); 7.47 (m, 4H, phenylCH);2.46 (s, 3H, CH₃).

Synthesis of 2-Methyl-3-(4-chloro-phenyl)-thienylcarbonyc dimeethylamide

[0100]

[0101] 15.3 g (0.06 mol) of acid, 7.1 ml SOCl₂ (0.1 mmol), 0.1 ml DMFand 100 ml of dichloromethane were placed into the bulb and refluxed in30 min. Then the mixture was evaporated. Resulting oil was dissolved in20 ml THF and this solution was added dropwise to 50 ml 33% aqueousMe₂NH at 0° C. The mixture was stirred in 30 min. The resulting emulsionwas poured into 500 ml of water. Product was extracted with 2×50 mldichloromethane. Solution was washed with water, dried over magnesiumsulfate and evaporated to give brown viscous liquid. Yield 14.4 g (86%).

[0102]¹H-NMR (CDCl₃): 7.45-7.30 (m, 5H); 3.25 (br.s, 6H); 2.50 (s, 3H).

[0103] Step a)1-[5-Methyl-4-(4-chloro-phenyl)-2-thienyl]-2-methyl-2-propen-1+L-ON

[0104] 7.2 g (26 mmol) of 2-methyl-3-(p-Cl-phenyl)-thienylcarbonic aciddimethylamide was dissolved in 15 ml THF and the resulting solution wasadded dropwise to solution of 2-propenylmagnesium bromide prepared from1 g Mg (42 mmol) and 3.7 g 2-bromopropene (31 mmol) in 20 ml THF at 0°C. The mixture warmed to r.t. and was stirred in 4 h. The resultingsolution was poured into 100 ml of 5% aqueous HCl. The organic layer wascollected, washed with water, dried over MgSO₄ and evaporated to givequantitative amount yellow-reddish oil that was used without furtherpurification.

[0105]¹H NMR (CDCl₃): 7.56 (s, 1H); 7.39 (AA′BB′ component, 2H); 7.29(AA′BB′ component, 2H); 5.79 (m, 1H), 5.74(m, 1H), 2.51 (s., 3H); 2.04(m, 3H)

[0106] Step b)2,5-Dimethyl-3-(4-chloro-phenyl)-4,5-dihydro-6H-cyclopenta[b]thiophen-6-on

[0107] Vinyl-ketone obtained in previous experiment was dissolved in 10ml of dichloromethane and resulting solution was poured into 25 mlmethanesulphonic acid heated to 65° C. After 20 min of stirring atreflux the resulting mixture was poured into the mixture 0.21water/ice/50 ml dichlorometane. The organic phase was collected, washedwith water, then with aq. NaHCO₃ up to neutral reaction and dried overMgSO₄. The resulting solution was evaporated and was purified bychromatography (hexane/ether 3/1) to give 2.2 g (31%) of viscous oil.

[0108]¹H NMR (CDCl₃): 7.41 (AA′BB′ component, 2H); 7.23 (AA′BB′component, 2H); 3.13 (dd, 1H), 2.94 (quintet of doublets, 1H); 2.50 (s,3H); 2.49 (dd, 1H), 1.31 (d, 3H)

[0109] Steps c) and d) Synthesis of2,5-dimethyl-3-(4-chloro-phenyl)-6H-cyclopenta[b]thiophene

[0110] ution of 2.2 g (8 mmol)2,5-dimethyl-3-(4-chloro-phenyl)-4,5-dihydro-6H-cyclopenta[b]thiophen-6-onin 20 ml ether was treated with 0.1 g (2.6 mmol) LiAlH₄ in 20 ml ether.The mixture was stirred in 30 min and then was poured in 30 ml of 10%NH₄Cl. The organic phase was collected, dried over MgSO₄ and evaporated.Resulting alcohol was dissolved in 150 ml benzene. To this solution 0.1g p-toluenesulphonic acid. The resulting mixture was refluxed in 10 min,then was cooled to r.t., washed with saturated aq. NaHCO3 and water. Thesolution so-obtained was dried over MgSO₄ and evaporated to give 1.4 g(67% from ketone) of the solid product.

[0111]¹H NMR (CD₂Cl₂): 7.37 (AA′BB′ component, 2H); 7.32 (AA′BB′component, 2H); 6.38 (quintet, 1H); 3.06 (br.s., 2H); 2.43 (s, 3H); 2.10(br.s, 3H).

Example 4 One Pot Synthesis of2,5-dimethyl-3-(4-chloro-phenyl)-6H-cyclopenta[b]thiophene lithium salt

[0112]

[0113] 15.3 g (0.06 mol) of acid, 7.1 ml SOCl₂ (0.1 mmol), 0.1 ml DMFand 100 ml of dichloromethane were placed into the bulb and refluxed in30 min. Then the mixture was evaporated. Resulting oil was dissolved in20 ml THF and this solution was added dropwise to 50 ml 33% aqueousMe₂NH at 0° C. The mixture was stirred in 30 min. The resulting emulsionwas poured into 500 ml of water. Product was extracted with 2×50 mldichloromethane. Solution was washed with water, dried over magnesiumsulfate and evaporated to give brown viscous liquid.

[0114] Viscous liquid so-obtained was dissolved in 15 ml THF and theresulting solution was added dropwise to solution of 2-propenylmagnesiumbromide prepared from 2 g Mg (42 mmol) and 7.4 g 2-bromopropene (62mmol) in 40 ml THF at 0° C. The mixture warmed to r.t. and was stirredin 4 h. The resulting solution was poured into 200 ml of 5% aqueous HCl.The organic layer was collected, washed with water, dried over MgSO₄ andevaporated to give yellow-reddish oil of vinil-ketone.

[0115] Vinyl-ketone obtained in previous experiment was dissolved in 20ml of dichloromethane and resulting solution was poured into 50 mlmethanesulphonic acid heated to 65° C. After 20 min of stirring atreflux the resulting mixture was poured into the mixture 0.41water/ice/100 ml dichlorometane. The organic phase was collected, washedwith water, then with aq. NaHCO₃ up to neutral reaction and dried overMgSO₄. The resulting solution was evaporated, then was dissolved in 50ml ether was treated with 675 mg (15 mmol) LiAlH₄ in 50 ml ether. Themixture was stirred in 30 min and then was poured in 30 ml of 10% NH₄Cl.The organic phase was collected, dried over MgSO₄ and evaporated.Resulting alcohol was dissolved in 300 ml toluene. To this solution 0.2g p-toluenesulphonic acid was added. The resulting mixture was heatedunder stirring at 80° C. in 10 min, then was cooled to r.t., washed withsaturated aq. NaHCO₃ and water. The solution so-obtained was dried overMgSO₄ and evaporated to give 10.4 g of crude ligand.

[0116] This crude product was dissolved in the mixture of 301 ml etherand 100 ml hexane and then was treated with 38 ml of 1.6M BuLi in hexane(60 mmol). The precipitate was isolated, washed with hexane and dried.Yield 7.5 g.

1. (currently amended) A process for preparing heterocyclic pentalenederivatives having formula (I):

wherein W is a sulfur atom, an oxygen atom or a NR or PR group wherein Ris selected from the group consisting of a linear or branched saturatedor unsaturated C₁-C₂₀-alkyl, C₃-C₂₀-cycloalkyl, C₆-C₂₀-aryl,C₇-C₂₀-alkylaryl and C₇-C₂₀-arylalkyl radical, optionally containingheteroatoms belonging to groups 13-17 of the Periodic Table of theElements; R¹, R², R³ and R⁴, equal to or different from each other, arehydrogen atoms or a linear or branched saturated or unsaturatedC₁-C₂₀-alkyl, C₃-C₂₀-cycloalkyl, C₆-C₂₀-aryl, C₇-C₂₀-alkylaryl orC₇-C₂₀-arylalkyl radical, optionally containing heteroatoms belonging togroups 13-17 of the Periodic Table of the Elements; or R¹ and R² and/orR³ and R⁴ can form a C₄-C₇ ring optionally containing O, S, N, P or Siatoms, said ring optionally bearing C₁-C₂₀ alkyl substituents or beingoptionally fused with a C₄-C₇ ring optionally containing O, S, N, P orSi atoms; said process comprising the following steps: a) contacting acompound of formula (II):

wherein R¹ and R² are defined as above and T is a OR, NR₂, OH, CCl₃,CF₃, Cl, Br, I, imidazolyl or pirazolyl radical[[;]], with at least onemolar equivalent of a vinyl compound of formula (III):

wherein R³ and R⁴ are defined as above and M is MgHal, Li, K, or ZnHal,and wherein Hal is chlorine, bromine or iodine[[;]], to form a compoundof formula (IV):

b) treating the compound of formula (IV) with a Brønsted acid to form acompound of formula (V):

c) treating the compound of formula (V) with a reducing agent to formthe correspondent alcohol of formula (VI)[[;]]:

d) dehydrating the alcohol of formula (VI).
 2. (currently amended) Theprocess according to claim 1 wherein in the compound of formula (I), thegroup NR is N-methyl or N-phenyl; the group PR is P-methyl or P-phenyl;R¹ is hydrogen, a C₁-C₂₀-alkyl or C₇-C₂₀-arylalkyl radical; R² ishydrogen or a C₇-C₂₀-arylalkyl radical; R³ is hydrogen or a C₁-C₂₀-alkylradical and R⁴ is hydrogen, a C₁-C₂₀-alkyl or C₇-C₂₀-arylalkyl radical.3. (currently amended) The process according to claim 1 claims 1 or 2wherein in the compound of formula (I), W is a sulfur atom; R¹ is amethyl, a phenyl or a C₁-C₁₀ alkyl substituted phenyl radical; R² is aphenyl or a C₁-C₁₀ alkyl-substituted phenyl radical and R⁴ is a methyl,or a phenyl radical.
 4. (currently amended) The process according toclaim 1 anyone of claims 1 to 3 wherein in the compound of formula (II),T is a NR₂ group and in the compound of formula (III), the group M isMgBr or Li.
 5. (currently amended) The process according to claim 1anyone of claims 1 to 4 wherein the Brønsted acid used in step b) aremethanesulphonic acid, sulfuric acid, phosphoric acid, polyphosphoricacid or P₂O₅/methansulfuric acid.
 6. (currently amended) The processaccording to claim 1 anyone of claims 1 to 5 wherein the reducing agentused in step c) is LiAlH₄, AlH₃, NaBH₄ or LiHAl(OtBu)₃.
 7. (currentlyamended) The process according to claim 1 anyone of claims 1 to 6wherein the dehydrating agent used in step d) is p-toluenesulfonic acid,sulfuric acid, hydrochloric acid or iodine.
 8. (currently amended) Theprocess according to claim 1 anyone of claims 1 to 7 wherein thecompound obtained in step d) is purified by treating the crude reactionproduct with at least one equivalent of an organolithium compound andfiltering the obtained salt.
 9. (currently amended) The processaccording to claim 1 anyone of claims 1 to 8 wherein steps a), b), c)and d) a), b, c) and) d) are carried out in sequence withoutpurification of the intermediate products.
 10. (currently amended) Theprocess according to claim 1 anyone of claims 1 to 8 wherein steps c)and d) are carried out without purification of the alcohol of formula(VI).